ertugliflozin/sitagliptin (Rx)

Brand and Other Names:Steglujan
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Dosing & Uses

AdultPediatricGeriatric

Dosage Forms & Strengths

ertugliflozin/sitagliptin

tablet

  • 5mg/100mg
  • 15mg/100mg

Type 2 Diabetes Mellitus

Indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus when treatment with both ertugliflozin and sitagliptin is appropriate

5 mg/100 mg PO qDay in morning initially; if additional glycemic control is needed and starting dose is tolerated, may increase to maximum dose of 15 mg/100 mg

Patients on ertugliflozin: Maintain ertugliflozin dose when switched to combination

Dosage Modifications

Concomitant use with insulin and insulin secretagogues may increase the risk of hypoglycemia; lower dose of insulin or insulin secretagogue may be required to minimize the risk of hypoglycemia when used in combination with ertugliflozin

Renal impairment

  • eGFR ≥60 mL/min/1.73 m²: No dosage adjustment necessary
  • eGFR <30 mL/min/1.73 m²: Contraindicated
  • End-stage renal disease or dialysis: Contraindicated
  • eGFR 30-60 mL/min/1.73 m²
    • Initiation of ertugliflozin not recommended
    • Continued use not recommended with persistent eGFR 30-60 mL/min/1.73 m²

Hepatic impairment

  • Mild-to-moderate: No dosage adjustment necessary
  • Severe: Not recommended

Dosing Considerations

In patients with volume depletion, correct this condition before initiating

Limitations of use

  • Not recommended in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis
  • Has not been studied in patients with a history of pancreatitis; unknown whether the drug increases risk for the development of pancreatitis

<18 years: Safety and efficacy not established

≥65 years: No dosage adjustment necessary

Patients aged ≥65 years had a higher incidence of adverse reactions related to volume depletion compared with younger patients

Elderly patients are more likely to have decreased renal function; because renal function abnormalities can occur after initiating ertugliflozin, and sitagliptin is known to be substantially excreted by the kidneys, renal function should be assessed more frequently

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Interactions

Interaction Checker

and ertugliflozin/sitagliptin

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    Contraindicated

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            Adverse Effects

            >10% (Ertugliflozin)

            Female genital mycotic infections (9.1-12.2%)

            1-10% (Ertugliflozin)

            Volume depletion adverse effects (1.9-4.4%)

            Male genital mycotic infections (3.7-4.2%)

            Urinary tract infections (4-4.1%)

            Headache (2.9-3.5%)

            Vaginal pruritus (2.4-2.8%)

            Increased urination (2.4-2.7%)

            Nasopharyngitis (2-2.5%)

            Back pain (1.7-2.5%)

            Renal adverse effects (1.3-2.5%)

            Weight decreased (1.2-2.4%)

            Thirst (1.4-2.7%)

            Frequency Not Defined (Sitagliptin)

            Upper respiratory tract infection

            Nasopharyngitis

            Headache

            Abdominal pain

            Nausea

            Diarrhea

            Peripheral edema

            Postmarketing Reports (Sitagliptin)

            Hypersensitivity including anaphylaxis, angioedema, rash, urticaria, cutaneous vasculitis, and exfoliative skin conditions

            Hepatic enzyme elevations

            Acute pancreatitis

            Worsening renal function and acute renal failure

            Bullous pemphigoid

            Constipation

            Vomiting

            Headache

            Myalgia

            Pain in extremity

            Back pain

            Pruritus

            Rhabdomyolysis

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            Warnings

            Contraindications

            Hypersensitivity

            Severe renal impairment, end-stage renal disease, or dialysis

            Cautions

            Acute pancreatitis, including fatal and nonfatal hemorrhagic or necrotizing pancreatitis, in patients taking sitagliptin reported; promptly discontinue if pancreatitis suspected

            Necrotizing fasciitis of the perineum (Fournier gangrene) reported with SGLT2 inhibitors; signs and symptoms include tenderness, redness, or swelling of the genitals or the area from the genitals back to the rectum, and have a fever above 100.4 F or a general feeling of being unwell; if suspected, discontinue SGLT2 inhibitor and start treatment immediately with broad-spectrum antibiotics and surgical debridement if necessary

            Causes intravascular volume contraction; symptomatic hypotension may occur after initiating, particularly in patients with renal impairment, with low systolic blood pressure, on diuretics, or who are elderly

            Ketoacidosis, a serious life-threatening condition requiring urgent hospitalization, reported; before initiating, consider factors that may predispose patient to ketoacidosis, including pancreatic insulin deficiency from any cause, caloric restriction, and alcohol abuse; monitor for ketoacidosis and temporarily discontinue in clinical situations known to predispose to ketoacidosis (eg, prolonged fasting owing to acute illness or surgery)

            Renal impairment may occur owing to intravascular volume contraction; before initiating, consider factors that may predispose patients to acute kidney injury, including hypovolemia, chronic renal insufficiency, CHF, and concomitant medications (eg, diuretics, ACE inhibitors, ARBs, NSAIDs); consider temporarily discontinuing ertugliflozin in any setting of reduced oral intake or fluid loss; monitor for signs and symptoms of acute kidney injury, and, if evident, discontinue drug promptly and institute treatment

            Serious urinary tract infections, including urosepsis and pyelonephritis, requiring hospitalization reported in patients receiving SGLT2 inhibitors

            An increased risk for lower limb amputation (primarily of the toe) has been observed in clinical studies with another SGLT2 inhibitor; before initiating, consider factors that may predispose patient to increased risk of amputations (eg, history of prior amputation, peripheral vascular disease, neuropathy, diabetic foot ulcers)

            Heart failure has been observed in cardiovascular outcomes trials for 2 other DPP-4 inhibitors; consider the risks and benefits prior to initiating treatment in patients at risk for heart failure (eg, those with a prior history of heart failure, a history of renal impairment), and observe these patients for signs and symptoms of heart failure during therapy

            Genital mycotic infections may occur; patients with history of genital mycotic infections and uncircumcised males are more susceptible

            Serious hypersensitivity reported with sitagliptin, including anaphylaxis, angioedema, and exfoliative skin conditions, including Stevens-Johnson syndrome (see Contraindications)

            Dose-related increases in LDL-C reported

            Severe and disabling arthralgia reported in patients taking DDP-4 inhibitors; may occur at any time; symptoms relieved upon discontinuation

            Bullous pemphigoid requiring hospitalization reported with DPP-4 inhibitors; patients typically recovered with topical or systemic immunosuppressive treatment and discontinuation of the DPP-4 inhibitor

            No conclusive evidence of macrovascular risk reduction with empagliflozin or any other antidiabetic agent

            Drug interaction overview

            • Hypoglycemia risk increased with insulin and insulin secretagogues (eg, sulfonylureas); a lower dose of insulin or insulin secretagogue may be required
            • Monitoring glycemic control with urine glucose tests is not recommended in patients taking SGLT2 inhibitors, as SGLT2 inhibitors increase urinary glucose excretion and lead to positive urine glucose tests; use alternative methods to monitor glycemic control
            • Monitoring glycemic control with 1,5-AG assay is not recommended, as measurements of 1,5-AG are unreliable in assessing glycemic control in patients taking SGLT2 inhibitors; use alternative methods to monitor glycemic control
            • Coadministration with sitagliptin has shown a slight increase in digoxin AUC (11%) and mean peak drug concentration (18%); no dosage adjustment of digoxin require, but monitor appropriately
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            Pregnancy

            Pregnancy

            Ertugliflozin

            • Based on animal data showing adverse renal effects, not recommended during the second and third trimesters of pregnancy
            • Data are limited in pregnant women and are not sufficient to determine a drug-associated risk of adverse developmental outcomes; there are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy
            • Animal data
              • In animal studies, adverse renal changes were observed in rats when ertugliflozin was administered during a period of renal development corresponding to the late second and third trimesters of human pregnancy; doses ~13 times the maximum clinical dose caused renal pelvic and tubule dilatations and renal mineralization that were not fully reversible
              • There was no evidence of fetal harm in rats or rabbits at exposures of ertugliflozin ~300 times higher than the maximal clinical dose of 15 mg/day when administered during organogenesis

            Sitagliptin

            • There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to sitagliptin during pregnancy
            • Health care providers are encouraged to report any prenatal exposure by calling the Pregnancy Registry at 1-800-986-8999

            Lactation

            Not recommended while breastfeeding

            Unknown if distributed in human breast milk

            Since human kidney maturation occurs in utero and during the first 2 years of life when lactational exposure may occur, there may be risk to the developing human kidney

            Because of the potential for serious adverse reactions in a breastfed infant, advise women that ertugliflozin/sitagliptin is not recommended while breastfeeding

            Pregnancy Categories

            A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

            B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

            C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

            D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

            X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

            NA: Information not available.

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            Pharmacology

            Mechanism of Action

            Ertugliflozin: Selective sodium-glucose transporter-2 (SGLT2) inhibitor; lowers the renal glucose threshold (ie, the plasma glucose concentration which exceed the maximum glucose reabsorption capacity of the kidney); lowering the renal glucose threshold results in increased urinary glucose excretion

            Sitagliptin: Dipeptyl peptidase-IV (DPP-4) inhibitor; increases and prolongs incretin hormone activity, which is inactivated by DPP-4 enzyme; incretins increase insulin release and synthesis from pancreatic beta cells and reduce glucagon secretion from pancreatic alpha cells

            Absorption

            Ertugliflozin

            • Peak plasma time: 1 hr (fasting); 2 hr (high-fat, high-caloric meal)
            • Peak plasma concentration, steady-state: 81.3 ng/mL (5 mg qDay); 268 ng/mL (15 mg qDay)
            • AUC, steady-state: 398 ng⋅hr/mL (5 mg qDay); 1,193 ng⋅hr/mL (15 mg qDay)
            • Steady-state is reached after 4-6 days
            • Bioavailability, 15 mg dose: ~100%

            Sitagliptin

            • Peak plasma time: 1 hr
            • Bioavailability: 87%

            Distribution

            Ertugliflozin

            • Vd, steady-state: 85.5 L
            • Protein binding: 93.6%
            • Blood-to-plasma concentration ratio of ertugliflozin: 0.66

            Sitagliptin

            • Vd: 198 L
            • Protein binding: 38%

            Metabolism

            Ertugliflozin

            • Major metabolic pathway for ertugliflozin is UGT1A9 and UGT2B7-mediated O-glucuronidation to 2 glucuronides (pharmacologically inactive at clinically relevant concentrations)
            • CYP-mediated (oxidative) metabolism of ertugliflozin is minimal (12%)

            Sitagliptin

            • Primary enzyme responsible for the limited metabolism of sitagliptin was CYP3A4, with contribution from CYP2C8

            Ertugliflozin

            • Half-life: 16.6 hr
            • Clearance: 11.2 L/hr
            • Excretion, oral [14C]-ertugliflozin solution: Feces (40.9%); urine (50.2%)
            • Excretion, unchanged ertugliflozin: Feces (33.8%); urine (1.5%)

            Sitagliptin

            • Half-life: 12.4 hr
            • Renal clearance: 350 mL/min
            • Excretion: 87% urine; 13% feces
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            Administration

            Oral administration

            Take in the morning qDay, with or without food

            Missed dose

            • Take it as soon as you remember
            • If it is almost time for scheduled next dose, skip missed dose and take the next regularly scheduled time
            • Do not take 2 doses of ertugliflozin at the same time

            Storage

            Store at room temperature between 68-77°F (20-25°C)

            Keep tablets dry

            Store blister packs in the original package

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            Formulary

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            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
            2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
            3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
            4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
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            NC NOT COVERED – Drugs that are not covered by the plan.
            Code Definition
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            Medscape prescription drug monographs are based on FDA-approved labeling information, unless otherwise noted, combined with additional data derived from primary medical literature.